This R01 application is in response to RFA-DE-07-002 to study the long-term use of antiretroviral therapy (ART) on the oral mucosa. Specifically, we will investigate how changes in the oropharyngeal tissues contribute to the pathogenesis of the human herpes viruses HSV-1, EBV and KSHV. These human pathogens cause different disease phenotype ranging from tissue destructive viremia (HSV-1) to oral cancer (KSHV, EBV). Regardless though of the final pathology, reactivation from a viral latent state seems to precede disease, and in case of EBV and KSHV many of the disease phenotypes are caused by gene products that are only expressed during viral reactivation. We hypothesize that (a) changes in the oral mucosal epithelial surfaces cause virus reactivation and (b) that ART modulates both the physiological trigger and the viral gene profile leading to ART-associated viral diseases such as oral KS, which is hardly seen in HIV-negative, ART-negative so called classic KS patients or EBV-positive plasmablastic lymphomas of the lower jaw. Furthermore, we will explore the effect of ART drugs on the innate immune response, i.e. TLR signaling by using our recently developed NF-kappaB real-time QPCR array to compare both clinical samples and experimental models of buccal and gingival epithelium.